Pharmaceutical formulations containing corticosteroids for topical administration

ABSTRACT

Pharmaceutical compositions for topical application to skin are provided. In some embodiments, the pharmaceutical compositions comprise a corticosteroid and further comprise a liquid oil component comprising one or more dicarboxylic acid esters and/or monocarboxylic acid esters.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/340,367, filed Jul. 24, 2014, which is a continuation of U.S. patentapplication Ser. No. 13/287,176, filed Nov. 2, 2011, issued as U.S. Pat.No. 8,809,307, which claims priority to U.S. Provisional PatentApplication Ser. No. 61/458,339, filed on Nov. 22, 2010.

BACKGROUND OF THE INVENTION

Topical corticosteroids are used to treat many acute and chronicdermatologic and mucosal disorders, especially those in which pruritusor inflammation is present. Many such conditions, such as eczema,psoriasis, and chronic dermatitis, such as hand dermatitis, are chronicconditions that require long-term therapy.

Corticosteroids for topical application are grouped within aclassification system into seven classes based on potency. Topicalpotency of a corticosteroid is determined by a standard test, referredto as a VasoConstrictor Assay (VCA). The VCA test is described in Dow etal, U.S. Pat. No. 7,300,669, incorporated herein by reference.

Table 1 shows the classification of topical corticosteroids based onpotency as determined by the VCA test.

TABLE 1 Potency Chart of Topical Corticosteroids Class 1-SuperpotentClobetasol propionate 0.05% Betamethasone dipropionate ointment 0.05%Halobetasol propionate 0.05% Fluocinonide 0.1% Diflorasone diacetateointment 0.05% (Psorcon ®) Class 2-Potent Betamethasone dipropionatecream 0.05% Mometasone furoate ointment 0.1% Diflorasone diacetate cream0.05% (Psorcon ®) Diflorasone diacetate ointment 0.05% (Florone ®)Halcinonide 0.1% Desoximetasone cream/ointment 0.25% Desoximetasone gel0.05% Fluocinonide cream/gel/ointment 0.05% (Lidex ®) Amcinonide 0.1%Budesonide 0.025% Beclomethasone 0.025% Class 3-Upper Mid-strengthFluticasone propionate ointment 0.005% Fluocinonide cream 0.05%(Lidex-E ®) Betamethasone valerate 0.12% Desoximetasone cream 0.05%Class 4-Mid-strength Flurandrenolide ointment 0.05% Mometasone furoatecream 0.1% Triamcinolone acetonide 0.1% Fluocinolone acetonide 0.03%Hydrocortisone valerate 0.2% Class 5-Lower Mid-strength Fluocinoloneacetonide shampoo 0.01% Flurandrenolide cream/lotion/tape 0.05%Fluticasone propionate cream/lotion 0.05% Prednicarbate cream 0.1%Desonide lotion 0.05% Hydrocortisone butyratecream/lotion/ointment/solution 0.1% (Locoid ®) Hydrocortisone probutatecream 0.1% (Pander ®) Fluocinolone acetonide cream 0.03%/0.01%(Synalar ®) Hydrocortisone valerate cream 0.2% Class 6-MildAlclometasone dipropionate 0.05% Fluocinolone acetonide oil 0.01%Desonide gel 0.05% Fluocinonide cream/solution 0.01% Desonide foam 0.05%Class 7-Least Potent Hydrocortisone lotion 0.5%/1% Hydrocortisonecream/spray/ointment 1% Hydrocortisone cream lotion 1%/2.5%

The most potent group of corticosteroids, determined on the basis of theVCA, is denoted Class 1 superpotent corticosteroids. In thisspecification, when a concentration is indicated with a particularcorticosteroid, for example as an ester, an acetonide, a free alcohol,or a diester, the corticosteroid is stated as a particular form of thecorticosteroid. When no concentration is indicated with acorticosteroid, or when a concentration refers to the corticosteroid inmore than one form, such as an ester, an acetonide, a free alcohol, or adiester, the corticosteroid is stated without reference to theparticular form. All known preparations of clobetasol propionate andhalobetasol propionate, all of which are at a concentration of 0.05%w/w, are classed as superpotent corticosteroids. Other corticosteroidsclassified as superpotent are certain preparations of betamethasonedipropionate at a concentration of 0.05%, diflorasone diacetate at aconcentration of 0.05%, and fluocinonide at a concentration of 0.1%. Thenext most potent group of corticosteroids is denoted Class 2 potentcorticosteroids. This group includes mometasone furoate at aconcentration of 0.1%, halcinonide, diflorasone diacetate,desoximetasone, fluocinonide at a concentration of 0.05%, and creamformulations of betamethasone at a concentration of 0.05%.

The superpotent corticosteroids are utilized for skin conditions thatare not satisfactorily responsive to lower potency corticosteroids. Suchconditions include psoriasis and certain severe types of eczema.Unfortunately, because of the high potency of the Class 1corticosteroids, which correlates with a high incidence and severity ofsystemic side effects, including hypothalamic-pituitary-adrenal (HPA)axis suppression, topical treatment with superpotent corticosteroids isgenerally limited in duration to 2 weeks. Such side effects may alsooccur with treatment with Class 2 potent corticosteroids. Additionally,the occurrence of local adverse reactions limits the duration of use ofsuperpotent and potent corticosteroids with respect to treatment ofchronic or recurrent skin diseases.

Chronic skin conditions, such as psoriasis, however often require longperiods of treatment, greater than 2 weeks, to manage such conditions.Therefore, it would be desirable to have a superpotent corticosteroidformulation with a reduced incidence and/or severity of systemic sideeffects so that therapy can be continued for durations longer than 2weeks.

Dow, U.S. Patent Publication 2006/0239929 discloses a spray formulationcontaining 0.05% clobetasol that was shown to be efficacious and to havefew serious side effects when administered for periods of 4 weeks. Thedisclosure of Dow, however, was limited to a spray formulation and theprosecution history of this application shows that prior artformulations of 0.05% clobetasol are associated with high frequencies ofserious systemic side effects, including hypothalamic-pituitary-adrenalaxis suppression when applied for a period of 2 weeks.

Because of the tendency of all superpotent corticosteroids to causeserious systemic effects, the FDA (Food and Drug Administration)requires that the prescribing information for currently marketed topicalcompositions of superpotent corticosteroids, such as clobetasol andhalobetasol, except for a particular spray formulation of clobetasol,carry the warning that treatment beyond 2 consecutive weeks is notrecommended, and the total dosage should not exceed 50 g of thecomposition per week. Regarding the clobetasol spray formulation, theprescribing information states that treatment should be limited to 4weeks and that treatment beyond 2 weeks should be limited to localizedlesions of moderate to severe plaque psoriasis that have notsufficiently improved after two weeks. Regarding potent corticosteroids,the FDA does not require the prescribing information to carry thiswarning, but does caution the physician to be aware of and to monitorfor the occurrence of HPA axis suppression.

Busse, U.S. Pat. No. 4,370,322, concerns the problem of systemic sideeffects due to topical application of high-potency corticosteroids.Busse discloses a topical pharmaceutical composition containing ahigh-potency corticosteroid and an oil phase that contains a lowviscosity oily solvent, wherein the concentration of the liquid oilphase is at least three times that which is required to completelysolubilize the corticosteroid. Busse discloses that, when thesolvent-containing oil phase is present in such high concentrationsrelative to the corticosteroid, the systemic absorption of thecorticosteroid is reduced but the local, desirable effects of thecorticosteroid are maintained. Busse further disclose that thisdiscovery permits the application of the same amount of steroid toachieve the same local anti-inflammatory effect while reducing unwantedsystemic effects.

Parab, U.S. Pat. No. 5,326,566, in contrast to the disclosure of Bussewhich discloses that a high concentration oily phase will decreasesystemic absorption of a corticosteroid when applied to the skin,discloses that, when a formulation contains a skin penetration enhancingamount of dibutyl adipate or a mixture of dibutyl adipate and isopropylmyristate at a concentration that is sufficient to dissolve thecorticosteroid in the formulation but which is less than 1.5 times thatwhich is required to dissolve the corticosteroid, the penetration of thecorticosteroid through skin and into the systemic circulation isincreased rather than decreased. Thus, Parab discloses that formulationscontaining a corticosteroid and an oily phase containing dibutyladipate, alone or in combination with isopropyl myristate, at aconcentration between 1 and 1.5 times that required to dissolve thecorticosteroid are useful for increasing the systemic absorption of atopically applied corticosteroid.

DESCRIPTION OF THE INVENTION

It has been unexpectedly discovered that the potency of a topicalcorticosteroid, including superpotent and potent topical corticosteroidas determined by VCA test described above, is maintained even when theconcentration of the corticosteroid is substantially reduced byproviding the corticosteroid in a formulation containing a liquid oilcomponent that includes a dicarboxylic acid ester and/or amonocarboxylic acid ester. Because the potency of the corticosteroid ismaintained, even when the concentration of the corticosteroid ismarkedly reduced, the desired dermatological effects of the treatmentare obtained. Due to the much reduced concentration of thecorticosteroid in the formulation, reduced amounts of corticosteroid areavailable to enter the systemic circulation and, therefore, the tendencyof such formulations to cause undesirable systemic side effects shouldlikewise be reduced. Thus, the formulations and methods of thisapplication are especially useful for the treatment of chronic orrecalcitrant skin diseases, such as psoriasis, due to the concernsregarding safety when topical corticosteroids are used in multiplecourse treatments over time.

Accordingly, one embodiment of the invention is a pharmaceuticalformulation for topical administration to the skin which contains acorticosteroid at a concentration below that which is presently utilizedin topical formulations and which provides substantially an equivalentpotency to formulations having the higher concentrations that arepresently utilized. Thus, for superpotent corticosteroids other thanfluocinonide, such as halobetasol propionate and clobetasol propionate,the formulation contains the corticosteroid at a concentration less than0.05% w/w and for fluocinonide the formulation contains thecorticosteroid at a concentration less than 0.05% w/w. Similarly, forpotent corticosteroids other than mometasone, halcinonide, andbeclomethasone, the formulation contains the corticosteroid at aconcentration less than 0.05%, and in the case of mometasone orhalcinonide, less than 0.1%, and in the case of beclomethasone, lessthan 0.025%.

The liquid oil component of the present application includes allingredients of the formulation that are practically insoluble orinsoluble in water and which are liquid at room temperature of 22° C.Other than the dicarboxylic acid ester and monocarboxylic acid estersdiscussed herein, the liquid oil component may contain additionalcomponents such as hydrocarbons like mineral oil, light mineral oil,squalene, and squalane, fatty alcohols such as octylododecanol andisostearyl alcohol, fatty acids such as isostearic acid and oleic acid,and triglycerides such as peanut oil, and fractionated coconut oil.

In addition to the liquid oil component, the formulation may containwater insoluble or practically insoluble ingredients that are not liquidat room temperature. However, as discussed in further detail below, itis the liquid oil component of the formulation that is of importance inrelation to the reduced concentration of the corticosteroid in theformulation.

The liquid oil component containing the dicarboxylic acid ester and/orthe monocarboxylic acid ester in the formulation is in association withthe corticosteroid in the formulation, such that the liquid oilcomponent and the corticosteroid may interact in the formulation inorder to dissolve or substantially dissolve the corticosteroid. It ishypothesized that it is this solubilization within the formulation that,upon application of the formulation to the skin of a patient, providesdelivery of the corticosteroid preferentially into the skin rather thanproviding transdermal delivery through the skin and into the systemiccirculation. As used herein, the term “substantially dissolve” meansthat the liquid oil component of a formulation of this invention candissolve 25% or more of the corticosteroid in the formulation at a roomtemperature of 22° C.

The corticosteroid that is included in the formulation of the inventionis preferably a superpotent corticosteroid according to theVasoConstrictor Assay (VCA), such as clobetasol, halobetasol,betamethasone dipropionate in augmented formulations, diflorasonediacetate in augmented formulations, and fluocinonide at 0.1%, or apotent corticosteroid, such as betamethasone dipropionate, mometasonefuroate, diflorasone diacetate, halcinonide, fluocinonide, anddesoximetasone.

Other steroids that are suitable for the formulation of the inventioninclude corticosteroids other than superpotent or potentcorticosteroids. Any corticosteroid that is suitable for topicalapplication to the skin or mucous membrane of a human may be thecorticosteroid of the formulation. The benefits of increased efficacy atlower concentration include reduced systemic exposure to thecorticosteroid, increased local as well as systemic safety, and reducedcost of materials for making the therapeutic corticosteroid formulation.These benefits are applicable to corticosteroids of any potency, such asa corticosteroid of potency classes 3 to 7, upper mid-strength to leastpotent. For example desonide gel or foam is a class 6 mildcorticosteroid and desonide lotion is a class 5 lower mid-strengthcorticosteroid. Desonide is widely used in children at a concentrationof 0.05%. It is conceived that a formulation containing a concentrationof desonide of less than 0.05% in which the potency is similar to thatof formulations containing 0.05% desonide would be especially useful inorder to reduce the total amount of steroid exposure experienced bychildren treated with desonide. Thus, included within the presentinvention are formulations containing concentrations of particularcorticosteroids below those shown in Table 1. For example, the inventionpertains to concentrations less than 0.005% for fluticasone propionate,concentrations less than 0.01% for fluocinolone acetonide,concentrations less than 0.025% for budesonide, beclomethasone, andtriamcinolone acetonide, concentrations less than 0.05% forflurandemolide, desonide, and aclometasone dipropionate, concentrationsless than 0.1% for amcinonide, betamethasone valerate, prednicarbate,hydrocortisone butyrate, and hydrocortisone probutate, andconcentrations less than 0.2% for hydrocortisone valerate. The inventionmay also be practiced with any form of a corticosteroid, such as anester, diester, free alcohol, or acetonide form of a corticosteroid.

The dicarboxylic acid ester (DCAE) that is suitable for the presentinvention has the formula R₁OOC—(CH₂)n-COOR₂, where R₁ and R₂ are alkylgroups containing between I and 4 carbons or aryl groups and may be thesame or may be different and where n is straight or branched and isbetween 1 and 12. Examples of DCAEs containing one or more aryl groupsare dibenzyl esters of dicarboxylic acids. A preferred dicarboxylic acidester is diethyl sebacate, which has the formulaCH₃CH₂OOC—(CH₂)₈—COOCH₂CH₃. Diethyl sebacate is considered to be typicalof the dicarboxylic acid esters disclosed as each of the parameters R₁,R₂, and n of diethyl sebacate are approximately in the center of therange of each of the specified parameters.

Examples of other suitable dicarboxylic acid esters where R₁═R₂ aredimethyl, diethyl, dipropyl, diisopropyl, dibutyl and diisobutyl esterssuch as oxalate, malate, succinate, glutarate, adipate, pimelate,suberate, and azalate. Examples of suitable dicarboxylic acid esterswhere R₁≠R₂ are methyl ethyl, methyl propyl, methyl butyl, methylisopropyl, ethyl propyl, ethyl butyl, ethyl isopropyl, and propyl butylesters such as oxalate, malate, succinate, glutarate, adipate, pimelate,suberate, azalate, and sebacate.

Alternatively, or in combination with the DCAE, the formulation maycontain a monocarboxylic acid ester (MCAE). The MCAE that is suitablefor the present invention has the formula CH₃—(CH₂)_(n)—COOR₁, where R₁,is an alkyl group containing between 1 and 4 carbons or an aryl group,and where n is straight or branched and is between 1 and 12. Examples ofsuch monocarboxylic acid esters include methyl, ethyl, propyl,isopropyl, butyl, or an aryl such as benzyl formate, acetate,propionate, butyrate, valerate, laurate, myristate, palmitate, andstearate. Examples of preferred monocarboxylic acid esters are isopropylpalmitate and isopropyl myristate.

The corticosteroid composition of the present invention may be anyformulation that incorporates DCAE and/or MCAE such as ointments,solutions, gels, foams and emulsions including creams and lotions.Preferably, the formulation is an emulsion in which an internal oilcomponent is dispersed within an external aqueous phase or an internalaqueous phase is dispersed within an external oil component. Examples ofemulsions include water-in-oil, oil-in-water, water-in-oil-in-wateremulsion, and oil-in-water-in-oil emulsions. The emulsion may be amacroemulsion, a microemulsion, or a nanoemulsion. Also contemplated areother formulations in which an oil phase and a water phase coexistwithin the formulation, such as a multivesicular emulsion, which is nota true emulsion, disclosed in Espinoza, U.S. Pat. No. 6,709,663. Alsocontemplated is a liposomal dispersion in which, preferably, the DCAE isincorporated in the lipid component of the liposomes. Also contemplatedare other formulations in which non-polar and polar liquid ingredientscoexist with the formulation.

Preferably, the formulation of the invention contains a thickening agentto provide viscosity so that the formulation may be provided in the formof a lotion, gel, cream, or ointment. Preferably but not necessarily,the thickening agent is miscible or soluble in an aqueous fluid.Examples of suitable thickening agents include acacia, alginic acid,bentonite, carbomers, also known as carboxy vinyl polymers, such as soldunder the tradename Carbopol® (Lubrizol, Wickliffe, Ohio),carboxymethylcellulose, ethylcellulose, gelatin, hydroxyethylcellulose,hydroxypropyl cellulose, magnesium aluminum silicate, methylcellulose,poloxamers, polyvinyl alcohol, sodium alginate, tragacanth, and xanthangum. The thickening agent may also reside in the oil or lipophilicportion of the formulation. Examples of suitable lipophilic thickeningagents include cetyl alcohol, stearyl alcohol, glyceryl stearate, whitebeeswax, microcrystalline wax, hydrogenated polyisobutane polymers, andemulsifying wax.

If desired or required in order to obtain the form of the formulationdesired, a surfactant or emulsifier may be included. The emulsifier ispreferably a non-ionic emulsifier such as a sorbitan ester, apolyoxyethylene derivative of a sorbitan ester or a glyceryl ester; apolymeric emulsifier such as a acrylates/C10-C30 alkyl acrylatecrosspolymer such as those sold under the tradename PEMULEN® (TheLubrizol Corporation, Wickliffe, Ohio); or an anionic emulsifier such asan alkali soap such as sodium or potassium oleate, an amine soap such astriethanolamine stearate, a detergent such as sodium lauryl sulfate,sodium dioctyl sulfosuccinate, and sodium docusate. Less preferred arecationic emulsifiers such as quaternary ammonium salts. Particularexamples of suitable anionic and non-ionic emulsifiers include glycerylmonostearate, polyoxyethylene monooleate, polyoxyethylene monostearate,polyoxyethylene monolaurate, potassium oleate, sodium lauryl sulfate,sodium oleate, sorbitan monolaurate, sorbitan monopalmitate, sorbitanmonostearate, sorbitan tristearate, sorbitan monooleate, sorbitantrioleate, triethanolamine oleate, polyoxyethylene sorbitan monolaurate,polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitanmonostearate, polyoxyethylene sorbitan tristearate, polyoxyethylenesorbitan monooleate, and polyoxyethylene sorbitan trioleate.

The formulation may contain other pharmaceutically acceptableexcipients. Preferably, the formulation contains a humectant such asglycerin, sorbitol, hexylene glycol, urea, or propylene glycol.Preferably, the formulation contains an emollient such as petrolatum,lanolin, mineral oil, light mineral oil, stearic acid, cyclomethicone,or dimethicone. Additional optional excipients include stabilizers,preservatives such as methylparaben, pH adjusting agents such as sodiumhydroxide, chelating agents such as EDTA and its salts, and buffers.

The formulation may include other lipophilic liquids in an amount thatis sufficient to be miscible with the dicarboxylic acid ester and/ormonocarboxylic acid ester. The lipophilic liquid may be an emollientsuch as lanolin oil, mineral oil, light mineral oil, isostearic acid,squalene, octyldodecanol, fractionated coconut oil, cyclomethicone, ordimethicone.

The formulation of the invention may be made by any method known to makea uniphase or multiphase pharmaceutical formulation for topicaladministration. In order to make a multiphase formulation such as anemulsion, for example, the components of the aqueous phase and of theoil phase may be separately combined and mixed until homogenoussolutions are obtained and then the aqueous solution and the oilsolution may be combined and mixed, such as by shear mixing, to form theformulation. The oil phase may be added to the water phase, or the waterphase may be added to the oil phase. The phases may be combined andmixed, such as at elevated temperatures of 50-90° C. or at roomtemperature, that is between 20-30° C., or at a temperature between roomtemperature and the elevated temperatures.

The formulation may be used for topical treatment or prophylaxis of adermatological or mucosal disorder that is responsive to the applicationof topical corticosteroids. Examples of such disorders includepsoriasis, dermatitis such as atopic, contact, or hand dermatitis,eczema, and poison ivy dermatitis.

The concentration of the corticosteroid in the formulation is that whichis sufficient to provide an anti-inflammatory response to an area ofskin or mucous membrane to which it is applied. The concentration mayvary depending on the particular disorder to be treated, the particularcorticosteroid utilized, and other parameters.

Because the primary purpose to which the invention is conceived topertain is to reduce the amount of corticosteroid that is available toenter the systemic circulation following the topical administration ofcorticosteroids, the preferred concentration of corticosteroid in theformulation of the invention is less than that present in prior arttopical formulations containing the same corticosteroid. For example,both clobetasol propionate and halobetasol propionate topicalformulations are presently available as creams and ointments in aconcentration of 0.05% w/w. Thus, it is preferred that the concentrationof such corticosteroid in the formulation of the present invention isless than 0.05% w/w. However, concentrations of corticosteroid at thesame level, that is at 0.05%, or higher, are not excluded from the scopeof the present invention unless indicated as such in the claims.

In a preferred embodiment, the formulation of the invention contains aconcentration of the corticosteroid such as clobetasol propionate orhalobetasol propionate that is 80% or less than that presentlyavailable, that is a concentration of 0.04% or less. In anotherpreferred embodiment, the formulation contains a concentration of thecorticosteroid that is 60% or less than that presently available, thatis a concentration of 0.03% or less. In another preferred embodiment,the concentration is 50% or less than that presently available, that isa concentration is 0.025% or less. In another preferred embodiment, theformulation of the invention contains a concentration of corticosteroidthat is 40% or less than that presently available, that is has aconcentration of 0.02% or less. In another preferred embodiment, theformulation contains a concentration of the corticosteroid that is 20%or less than that presently available, that is has a concentration of0.01% or less. In another preferred embodiment, the concentration ofcorticosteroid in the formulation of the invention is 10% or less thanthat presently available, that is 0.005% or less.

The concentration of the liquid oil component of the formulationcontaining a DCAE and/or an MCAE is at least that which is sufficient todissolve at least 25% of the entire amount of the corticosteroid in theformulation at a room temperature of 22° C. In one embodiment, theconcentration of the liquid oil component is sufficient to dissolvebetween 25% and 50% of the corticosteroid, such as about 40%. In apreferred embodiment, the concentration of the liquid oil component issufficient to dissolve between 50% and 60% of the corticosteroid, suchas about 55%. In another preferred embodiment, the concentration of theliquid oil component is sufficient to dissolve between 60% and 70% ofthe corticosteroid, such as about 65%. In another preferred embodiment,the concentration of the liquid oil component is sufficient to dissolvebetween 70% and 80% of the corticosteroid, such as about 75%. In anotherpreferred embodiment, the concentration of the liquid oil component issufficient to dissolve between 80% and 90% of the corticosteroid, suchas about 85%. In another preferred embodiment, the concentration of theliquid oil component is sufficient to dissolve between 90% and 100% ofthe corticosteroid, such as about 95%.

In a more preferred embodiment, the concentration of the liquid oilcomponent is sufficient to dissolve 100% or more of the corticosteroidin the formulation at a room temperature of 22° C. For example theconcentration of the liquid oil component may be between 1.0 and 1.5times that which is sufficient to dissolve the entire amount of thecorticosteroid in the formulation. For example, the concentration of theliquid oil component may be greater than 1.5 times that which issufficient to dissolve the entire amount of the corticosteroid in theformulation, such as between 1.5 times and 3.0 times that which issufficient to dissolve the amount of corticosteroid in the formulation.For example, the concentration of the liquid oil component may be morethan 3.0 times that which is sufficient to dissolve the entire amount ofthe corticosteroid in the formulation. Examples of suitableconcentrations of liquid oil component in terms of amount required todissolve the entire amount of corticosteroid in the formulation at roomtemperature include 0.25, 0.4, 0.5, 0.75, 1.0, 1.05, 1.15, 1.25, 1.25,1.24, 1.45, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, and 6.0 times orhigher than that which is sufficient to dissolve the corticosteroid inthe formulation at a room temperature of 22° C.

The combined concentrations of the DCAE and/or the MCAE in the liquidoil component of the formulation is at least about 10% of the oilcomponent, such as at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% ofthe oil component. In one preferred embodiment, the DCAE, and MCAE ifpresent, constitute 100% of the liquid oil component of the formulation.

The formulation of the invention maintains a VCA score as high or thatis similar to the VCA score that is obtained by the application of priorart formulations containing higher concentrations of the corticosteroid,such as the superpotent corticosteroid. Because the VCA score isdeterminative of local efficacy, the formulation of the invention, evenat greatly reduced concentrations of corticosteroid, would be understoodby one of skill in the art to be generally as effective locally in theskin as presently available formulations containing higherconcentrations of corticosteroid. Additionally, because of the reducedconcentration of corticosteroid in the formulation compared to that inthe prior art compositions and the concomitant reduction in amount ofcorticosteroid that is available to enter the systemic circulation upontopical administration of the formulation, it is conceived that theformulation may have similar efficacy but improved safety compared toprior art formulations that contain higher concentrations ofcorticosteroid. Thus the formulations of this application haveparticular utility in infants and children in treating skin diseasessuch as atopic dermatitis and in both adults and children for treatingrecalcitrant or chronic skin diseases such as psoriasis. It is conceivedthat the present invention provides an equivalent or better efficacy intreating steroid responsive skin diseases compared to that produced bypresently available topical formulations, and with potentially reducedlocal and systemic side effects.

The invention is further illustrated in the following non-limitingexamples. In the examples, halobetasol propionate is utilized as anexemplary superpotent corticosteroid and diethyl sebacate is utilized asan exemplary dicarboxylic acid ester. It is understood, however, thathalobetasol propionate is illustrative of the superpotent and potentcorticosteroids, that diethyl sebacate is illustrative of the DCAE, andthat isopropyl myristate is illustrative of the MCAE, and that anycorticosteroid, especially potent or superpotent corticosteroid, DCAE,or MCAE may be substituted for the illustrated halobetasol propionate,diethyl sebacate, and/or isopropyl myristate with similar results.

Example 1—Formulations

The following formulations as shown in Table 1 were made containing thesuperpotent corticosteroid halobetasol as halobetasol propionate (HP).Formulations A to D are formulations of the invention. Formulation E isa formulation that is not within the scope of the present invention.

TABLE 1 Formulation A B C D E Ingredients % w/w Halobetasol Propionate0.035 0.025 0.01 0.035 0.035 (corticosteroid) Diethyl Sebacate (DCAE)3.0 2.1 0.8 0.9 Isopropyl Myristate (MCAE) 11.0 Light Mineral Oil 1.00.7 0.3 Medium Chain Triglycerides 18.0 White Petrolatum 2.0 ButylatedHydroxytoluene 0.01 Sorbitan Monooleate 0.1 0.1 0.1 0.1 Cholesterol 0.5Stearyl Alcohol 1.0 Cetyl Alcohol 0.5 Propylene Glycol 7.5 7.5 7.5 7.57.5 Disodium Edetate Dihydrate 0.05 0.05 0.05 0.05 0.05 Pemulen ® TR-10.40 0.40 0.40 0.40 0.40 Carbopol ® 981 0.60 0.60 0.60 0.60 0.60Methylparaben 0.17 0.17 0.17 0.17 0.17 Propylparaben 0.03 0.03 0.03 0.030.03 Sodium Hydroxide q.s. pH 6.0 +/−1 Purified Water q.s.ad 100

Example 2—Determination of Saturation Solubility and Degree ofSaturation

The saturation solubility of halobetasol propionate in each offormulations A to D of Example 1 was determined as follows. At atemperatures of 22°+/−2° C., samples containing halobetasol in theliquid oil component components of formulations A to D, respectively,were prepared and stored in glass vials. The samples were shaken at 395to 405 oscillations/minute for approximately 72 hours using a BurrellWRIST-ACTION® Shaker Model 75 (Burrell Scientific, Pittsburgh, Pa.).Samples were then centrifuged for 40 minutes at 3500 rpm and thesupernatant was collected. The supernatant was filtered using 0.45 umPTFE ACRODISC® Pall syringe filter (Pall Corporation, Port Washington,N.Y.). The filtered samples were analyzed by HPLC using a reverse phasecolumn monitored at 254 nm UV detection. The degree of unsaturation ofhalobetasol propionate of each formulation was then calculated bymultiplying the concentration (% w/w) of the liquid oil component by thesaturation solubility of halobetasol in the liquid oil componentcomponents and dividing by the concentration of halobetasol propionatein the formulation. The data is shown below in Table 2.

TABLE 2 Concentration of Saturation Degree Liquid Oil Solubility ofFormulation component (% w/w) (% w/w) Unsaturation A 4 2.41 2.8 B 2.82.41 2.7 C 1.1 2.41 2.5 D 11.9 0.45 1.5

Example 3—Determination of VCA Scores

The mean VCA score of each of the formulations of Example 1 wasdetermined as described in Dow, U.S. Pat. No. 7,300,669 and was assigneda semi-quantitative subjective evaluation score on a scale of 0 to 4.The mean VCA score of a formulation corresponding to that of thecommercial product Ultravate® 0.05%; NDC 0072-1400-50 (Bristol-MeyersSquibb Company, Princeton, N.J.) was also determined. In contrast to theother formulations tested, Ultravate contains halobetasol propionate ata concentration of 0.05%. In determining the mean VCA score, theevaluator was blinded as to the formulation being tested. The resultsare shown in Table 3.

TABLE 3 Formulation HP Conc (% w/w) VCA Mean Score A 0.035 2.37 B 0.0252.40 C 0.010 2.47 D 0.035 2.43 E 0.035 1.77 Ultravate ® 0.050 2.37

As shown in Table 3, each of the formulations A to D of the presentinvention provided a VCA score similar to that of the prior artformulation Ultravate®. This high level of VCA score, which isindicative of the local desired response of the corticosteroid, wasobtained even though the level of corticosteroid in the formulations ofthe invention are markedly lower than that in the prior art formulation.Formulation E, which contained the same concentration of corticosteroidas in Formulations A and D, had a markedly lower VCA score.

Example 4—Lotion Formulations

Lotion formulations 4a and 4b of the present invention contain theingredients shown in Table 4. These formulations may be made as follows.

A separate aqueous phase is made. In a manufacturing vessel, purifiedwater and disodium edetate dihydrate are combined and the mixture isagitated until a clear solution is achieved. Sorbitol, methylparaben,and propylparaben are then added to the mixture. The mixture iscontinuously mixed and is heated to approximately 75° C. The mixture isagitated until a solution is obtained. The mixture is then removed fromthe heat source and allowed to cool to below 40° C. with continuedmixing. With continuous propeller agitation Carbopol 981 and PemulenTR-1 are added to the mixture and dispersed. The propeller mixing iscontinued until the polymers are fully dispersed and hydrated.

A separate oil phase is made. In a vessel diethyl sebacate andhalobetasol propionate are combined. The mixture is agitated until asolution is achieved. With continuous propeller mixing, light mineraloil and sorbitan monooleate are added. Mixing is continued until asolution is obtained.

In a separate vessel, a 1N solution of sodium hydroxide is prepared.

With high speed rotor-stator mixing, the oil phase containing the drug(halobetasol propionate) is added to the aqueous phase. Mixing iscontinued until a homogeneous emulsion is obtained. Propeller mixing isthen used in place of the high speed rotor-stator mixing. Withcontinuous mixing an appropriate amount of the sodium hydroxide solutionis added incrementally to obtain a pH of 5.5±0.5. Propeller mixing iscontinued until a homogeneous lotion is obtained.

TABLE 4 % w/w Ingredients Formula 4A Formula 4B Halobetasol Propionate0.01 0.025 Diethyl Sebacate 2.97 2.90 Light Mineral Oil 8.03 2.90Sorbitan Monooleate 0.10 0.10 Sorbitol Solution, 70% 10.7 10.7 DisodiumEdetate, Dihydrate 0.05 0.05 Pemulen TR-1 0.40 0.40 Carbopol 981 0.600.60 Methylparaben 0.17 0.17 Propylparaben 0.03 0.03 Sodium Hydroxide,q. s. pH 4.0-6.0 pH 4.0-6.0 Purified Water, q.s. ad 100 100

Example 5—Stability Data

A lotion formulation was made by the method of Example 4 using theingredients listed in Table 5.

TABLE 5 Ingredients Percent w/w Halobetasol propionate (HP) 0.025Diethyl Sebacate 2.10 Light Mineral Oil 0.70 Sorbitan Monooleate 0.10Propylene Glycol 7.50 Methylparaben 0.17 Propylparaben 0.03 EdetateDisodium, Dihydrate 0.05 Pemulen TR-1 0.40 Carbopol 981 0.60 SodiumHydroxide q.s. ad pH 5.0 Purified Water q.s. ad 100

The formulation was packaged in glass screw-cap jars and tested forstability at refrigerator temperature (5° C.), room temperature (25°C.), and accelerated temperature (40° C.) and tested at the beginning ofthe study and periodically for up to 6 months. Description was performedby visual observation, pH was measured with a calibrated pH meter, andviscosity was measured with a Brookfield rotational viscometer usingspindle 27 and a speed of 12 rpm. The content of halobetasol propionatewas determined by reverse phase HPLC using a C18 column and UVdetection. The stability specifications for the halobetasol lotion thatwould be required for a commercial product would typically be as shownin Table 6.

TABLE 6 PARAMETER FDA REQUIREMENT Description no substantial change pH4.0 to 6.0 Viscosity 7,500 to 15,000 cps HP Content 90 to 110% oflabeled amount

The physical and chemical stability test results for this formulationare indicated below in Table 7.

TABLE 7 Vis- HP Content Con- cosity (% of labeled dition TimeDescription pH (cps) amount) Initial 0 months White to off-White Lotion5.1 10,833 99.4  5° C. 6 months Conforms 5.1 12,285 94.0 25° C. 3 months5.1 12,140 95.3 6 months 5.1 13,215 92.1 40° C. 1 months 5.1 12,090 95.13 months 5.1 12,090 93.4 6 months 5.1 12,070 92.5

The HP lotion was determined to be within the typical specifications atall test times. The data of Table 6 indicates that this lotion productwould be expected to have a 2 year shelf life at room temperature basedon the favorable results after 6 months at 40° C.—the acceleratedcondition accepted by the Food and Drug Administration to support a 2year product shelf life at room temperature.

Further modifications, uses, and applications of the invention describedherein will be apparent to those skilled in the art. It is intended thatsuch modifications be encompassed in the following claims.

What is claimed is:
 1. A pharmaceutical composition for topicalapplication to the skin of an individual comprising: a liquid oilcomponent comprising one or more monocarboxylic acid esters and/ordicarboxylic acid esters, wherein the liquid oil component furthercomprises a corticosteroid selected from the group consisting ofhalobetasol propionate, clobetasol propionate, betamethasonedipropionate, and diflorasone diacetate at a concentration less than0.05% and fluocinonide at a concentration less than 0.1%, and wherein atleast 25% of the corticosteroid is solubilized in the liquid oilcomponent at a temperature of 22° C.±2° C.; and an aqueous componentcomprising water.
 2. The pharmaceutical composition of claim 1, whereinthe liquid oil component comprises one or more monocarboxylic acidesters.
 3. The pharmaceutical composition of claim 1, wherein the liquidoil component comprises one or more dicarboxylic acid esters.
 4. Thepharmaceutical composition of claim 1, wherein the liquid oil componentfurther comprises mineral oil or light mineral oil.
 5. Thepharmaceutical composition of claim 1, wherein the concentration of thecorticosteroid is 0.04% or less.
 6. The pharmaceutical composition ofclaim 1, wherein the corticosteroid is halobetasol propionate.
 7. Thepharmaceutical composition of claim 1, wherein the concentration of theliquid oil component is sufficient to dissolve the amount ofcorticosteroid in the composition at a temperature of 22° C.±2° C. 8.The pharmaceutical composition of claim 7, wherein the concentration ofthe liquid oil component is between 1.5 and 3 times that required tocompletely solubilize the amount of corticosteroid in the composition ata temperature of 22° C.±2° C.
 9. The pharmaceutical composition of claim8, wherein the concentration of the liquid oil component is between 1.75and 2.75 times that required to completely solubilize the amount ofcorticosteroid in the composition at a temperature of 22° C.±2° C. 10.The pharmaceutical composition of claim 1, wherein the liquid oilcomponent further comprises an emulsifying agent.
 11. The pharmaceuticalcomposition of claim 1, wherein the aqueous component further comprisesone or more humectants, preservatives, chelating agents, emulsifyingagents, and/or thickening agents.
 12. The pharmaceutical composition ofclaim 1, further comprising a pH adjusting agent.
 13. The pharmaceuticalcomposition of claim 1, wherein the composition is formulated as anoil-in-water emulsion, a water-in-oil emulsion, an oil-in-water-in-oilemulsion, or a multivesicular emulsion.
 14. The pharmaceuticalcomposition of claim 1, wherein the composition is formulated as alotion, a gel, a cream, or an ointment.
 15. A pharmaceutical compositionfor topical application to the skin of an individual comprising: aliquid oil component comprising one or more dicarboxylic acid esters andfurther comprising halobetasol propionate at a concentration less than0.05%, wherein at least 25% of the halobetasol propionate is solubilizedin the liquid oil component at a temperature of 22° C.±2° C.; and anaqueous component comprising water.
 16. The pharmaceutical compositionof claim 15, wherein the composition is formulated as a lotion, a gel, acream, or an ointment.
 17. A method of treating a disorder of the skinthat is amenable to treatment with a topical corticosteroid, the methodcomprising applying the pharmaceutical composition of claim 1 to theskin of an individual having the disorder in an amount that is effectivein ameliorating the signs or symptoms of the disorder.
 18. The method ofclaim 17, wherein the disorder is psoriasis, atopic dermatitis, contactdermatitis, hand dermatitis, eczema, or poison ivy dermatitis.
 19. Themethod of claim 17, wherein the method comprises applying thepharmaceutical composition over a period of treatment of up to twoweeks.
 20. The method of claim 17, wherein the method comprises applyingthe pharmaceutical composition over a period of treatment longer thantwo weeks.